The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages include the fewer side effects and greater potency often associated with enantiomerically pure compounds.
Traditional methods of organic synthesis were often optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); and the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming.
The ever-increasing industrial and academic demand for enantiopure chemicals has been accompanied by the development of numerous asymmetric synthetic methods utilizing highly efficient chiral catalysts and auxiliaries. For example, see: (a) Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E. (Eds.) Stereoselective Synthesis in Methods of Organic Chemistry, Houben-Weyl, Vol. 21, 4th edition., Thieme, Stuttgart, 1995; (b) Ojima, I. (Ed.) Catalytic Asymmetric Synthesis 2nd edition, Wiley-VCH, New York, 2000; (c) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008-2022; and (d) Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2024-2032. Ideally, a practical asymmetric catalyst is inexpensive, readily available in both enantiopure forms, and provides high yields and enantioselectivities for a wide range of substrates in various reactions. Among the many chiral catalysts reported to date, a relatively small number derived from rigid C2-symmetric ligands including BINOL, BOX, salen, DIOP, DUPHOS, and TADDOL have proved to be exceptionally versatile and effective.
Remarkably, as described herein, chiral catalysts derived from readily accessible rigid C2-symmetric chiral bisoxazolidines, which can be derived from amino alcohols and diketones, have been developed. In addition, their successful use in asymmetric bond-forming reactions has been demonstrated.